IL27968A - Alkyl 6,7-dialkoxy-4-hydroxyquinoline-3-carboxylates - Google Patents

Description

THIS INVENTION relates to new quinoline derivatives, to processes for their preparation, to compositions containing them, and to their use in the prevention of coccidiosis in chickens* Coccidiosis , a disease caused by infections by protozoan paratfitee of the genus Eimejria, is one of the most important potential causes of economic loss in chicken flocks, particularly those raised under intensive conditions. The disease has a world-wide incidence and may occur wherever poultry are reared, and, if left untreated, often causes extensive loss of fowl* Economic loss results not only from mortality of the infected birds but also morbidity which may manifest itself in depression of body growth rate, reduction of food conversion efficiency and a general deterioration which is found in the carcass at slaughter* The elimination or control of coccidiosis is, therefore, of the utmost importance in successful chicken raising* Although other species occur in the chicken, the following five species of Eimeria, namely Ε· tenella, E. acervulina, Ξ. necatrix, E. brunetti and E. maxima, arc generally regarded as being responsible for the economic losses due to coccidiosis in the rearing of chickens* Hitherto, the control of the disease has been effected by. the use of anti-coccidial drugs, generally administered in the feed to prevent outbreaks by inhibiting or slowing down the multi-plication of Eimeria within the birds, or by administration in drinking water to treat established disease. Coccidiostats which have been used commercially are of various chemical types, for example l~(4-amino-2-n-propyl-5-pyriraidinyl-methyl)-2-picolinium chloride hydrochloride (amproliura), 3,5-dinitro-o-toluamide (zoalene), 2-sulphanilamidoquinoxaline (sulphaquinoxaline) and 5-nitro-2-furaldehyde seraicarbazone (nitrofurazone) , and minor alterations in chemical structure have been found to alter substantially their usefulness and in some instances to reduce the anti-coccidial activity to such a degree that the compounds can no longer be used* The efficacy of the coccidiostats which ore in current wide scale use is, however, usually limited by the possession of a narrow spectrum of activity in terms of the species of Eimeria upon the species and severity of the challenge encountered) neither^of which can be predicted. Infections with E. tenel l i which is responsible for a severe infection of the cecum of chickens , and S. necatrix frequently result in mortality while infections due to the other three species are less frequent ly the cause of mortality but nevertheless result in economic loss due to depression of growth rate , feed-conversion efficiency and carcass deterioration* E, tenolla and E . necatrix have generally been regarded in the past as being the most important species and efforts in the selection of coccidiostats have been directed primarily towards the control of these species . In recent years it has been found , however , that while the control of E. tenella and E. necatrix remains an important problem , the incidence of disease caused by E, acervulina , E . maxima and S. brunetti has increased, thereby increasing the importance of their control . Hence , the limitations in usefulness of coccidiost ats having only a narrow spectrum of activity will be appreci ated. Furthermore , the use of mixtures containing two or more coccidiostats , although effective in increasing the spectrum of activity , results in an increase in the cost of medication. An additional problem, which is encountered in the control of coccidiosis and is of increasing import ance , is the emergence of strains of Simeria which are resi st ant to coccidiostats which normally control the species in question.

In addition to control ling the disease , it is naturally import ant that a coccidio3tat should be wel l tolerated at the dose levels which are used and should have no adverse effect upon the heal th of the birds to which it is administered.

Despite the success which has hitherto been achieved in controlling cocci diosis in chickens by medication, research has , therefore , been continued with the objective of discovering useful alternative coccidiost ats effective at an acceptably low concentration in the feed. Jleongst the various types of organic compounds that have been investigated in this connection are certain alkoxy-3ubstituted 4-hydroxyquinoline-3-carboxylic acid esters (see United States Patent No 26 106 ran o Edward John . Watson on 16th Au ust activity, both the nature and degree of useful effect (if any)can radically alter even with apparently small changes in chemical structure. More specifically, activity against E. tenella. E. acervulina and E. necatrix has been previously shown to be possessed by certain quinoline derivatives of the formula: wherein Q and ¾| each represent a straight- or branched-chain alkyl radical containing 2 to 4 carbon atoms and represents a lower alkyl group, the best of these compounds being ethyl 6,7-diisobutoxy-4-hydroxyquinoline-3-carboxylat< otherwise known as "Buquinolate". In marked contrast, . when there is an alkoxy group in the 6-position having 5 or 6 carbon atoms in a straight- or branched-chain, the anti-coccidial activity falls away markedly and, for example, the compounds in which Q is n-pentyl, n-hexyl or 2-ethyl-n-butyl, is methyl and (¾2 is ethyl possess, in relation to buquinolate, very low activity and are of no practical utility. Similarly of relatively very low activity are compounds in which Q and are both methyl groups or higher alkyl, for example n-octyl or n-decyl, or benzyl groups, and so is the compound ethyl 4-hydroxy-6-methoxy-7-n-octyloxyquinoline-3-carboxylate in which Q is a lower alkyl group and is a higher alkyl group.

In addition Israel Patent Kb. 25347, granted to Imperial Chemical Industries Limited, discloses the use as anti-coccidial agents of the broad class of quinoline derivatives of the formulas wherein R stands for an alkyl radical or for a phenyl or phenylalkyl radical 2 halogen atoms or alkyl or nitro radicals, R stands for an alkyl radical, and wherein the quinoline nucleus may optionally bear one or more additional substituents selected from halogen atoms, and alkyl, alkenyl and alkoxy 1 2 radicals , and provided that when both R and R stand for alkyl radicals of . not more than 4 carbon atoms , then the quinoline nucleus does not bear as sole additional substituent, an alkoxy radical of not more than 4 carbon atoms in the 6-position.

As the result of very extensive programme of research and investigation conducted by the present Applicants, it has now been found that a narrow class of new quinoline derivatives of the aforesaid general formula I within r the scope of the compounds of Israel Patent No. 25347, and differing from the compounds of United States Patent No. 3,267, 106 in that the groups Q and . are different alkyl groups, Q being a straight-chain alkyl group of 7 to 11 oarbon atoms and being a straight- or branched-chain alkyl group containing from 1 to 4 carbon atoms, possess an unexpectedly very high order of anticoccidial activity (the results of comparative experiments with other compounds within the disclosure of Israel Patent No. 25347 are given at the end of the specification) , and are useful for the prophylactic control of coccidiosis in chickens. The c ompounds of the present invention c omprise the quinoline derivatives of the general formula: (wherein R represents a straight-chain alkyl group containing from 7 to 11 carbon atoms , R^ represents a straight- or branched-chain alkyl gro3p containing from 1 to 4 carbon atoms , and R represents a straight- or branched-chain alkyl group cont aining from 1 to 3 carbon atoms ) and the salts of those derivatives* In contrn-distinction, the corresponding compounds in which R represents a straight-chain alkyl group containing 12 or more carbon atoms or a branched-chain alkyl group having 7 to 11 carbon atoms [e .g. -CH (CK_ )CH -CH2CH (CH3 )2, -CH (C2H5 )CH2CH2CK2CH2CH3 , -C^CH^HiCH^CH^C iCH^ and -CH CH CH (CH )CH CH CH CH (CH ) ] possess no significant anti-coccidial activity, The new coccidiostats of formula II are effective in the prophylactic control simultaneously of a number of Simeria causing both intestinal, and cecal coccidiosis in chickens * When administered at concentrations of 0,0001% to 0,05% (preferably 0.001% to 0.004%) by weight in a balanced chicken feed or drinking water to chickens exposed to coccidiosis , they inhibit the development of Simeria and therefore suppress the mortality and morbidity to which intestinal and cecal coccidiosis normally give rise , and consequently have a favourable effect on the weight gain of the birds . They are non-toxic and have no adverse effect upon the health of chickens at administration rates useful in the prevention of coccidiosis .

Preferred compounds of formula I are those in which R is an n-octyl , n-nonyl or n-decyl group , R^ is a methyl , ethyl , n-propyl , isopropyl or sec-butyl group , and R is a methyl or ethyl group . Speci fic compounds of particular value are methyl 7-othoxy-4-hydroxy-6-n-nonyloxyquinoline-3-carboxylate , ethyl 7-ethoxy-4-hydroxy-6-n-nonylo..yquinoline-3~carboxylate , methyl 4-hydroxy-7-isopropo..y-6-n-nonyloxyquinoline-3-carboxylate . ethyl 4-hydro.cy-7-isopropoxy-6-n-nonyloxyquinoline-3-carbo.cyl ate , methyl 6-n-decyloxy-4-hydroxy-7-isopropoxyquinoline-3-carbo.;ylate , ethyl 6-n-decyloxy-4-»hydro.cy-7»isopropoxyquinoline-3-carboxylato , ethyl 7-sec-butoxy-6-n-decyloxy-4-hydroxyquinoline-3-carboxylate , more particularly ethyl 4-hydroxy-7-methoxy-6-n-nonyloxyquinoline-3-corboxylatQ , ethyl 6-n-decyloxy-4- iydroxy-7-methoxy- uinoline-3-carbox late meth l 4-h drox -7-raethox -6-n-oct lox uinoline-3- hydroxy-7-raetho.Ly-6-n-nonylo: yquinoline-3-carbo3iylate , methyl 6-n-dec^.oxy-4-hydro3iy-7-methoxyquinoline-3-carboxylate , and especially ethyl 4-hydro.:y-7-isopropoxy-6-n-octyloxyquinoline-3-carbo. ylate , methyl 4-hydroxy-7-isopropo3cy-6-n-octyloxyquinoline-3-carbo3.ylate, methyl 7-ethoj_y-4-hydroxy-6-n-.octylo-.y-quinoline-3-carboxylate, methyl 6-n-decylo3.y-7-ethoxy-4-hydroxyquinoline-3-csrboxylote and ethyl 6-n-decyloxy-7-ethoxy-4-hydro3cyquinoline-3-carbo:!ylate , the last compound being of outstanding value.

According to a feature of the present invention, the new compounds of formula II arc prepared by the cyclisation of anilinoraethylenemalonete derivatives of the general formula: wherein R, R^ and R2 are as hereinbefore defined , by known methods for the formation of quinoline derivatives from anilinomethylenemalonates. Cyclisation may be effected for ejiample , by treatment v/ith an acid reagent , e .g. a mi.rture of acetic anhydride and sulphuric cid, or by heating the compound of formula o III at elevated temperature , for example from 180 to 350 C , and more particularly at from 200 to 280°C , advant geously in a suitable high boiling point solvent , for example a mineral oil , "Dowtherm" or "Diphyl" .

The derivatives of formula III may be prepared (i ) by reaction of an aniline of the general formula : (wherein R and R ore as hereinbefore defined) with a dialkyl alkoxymethylene-malonate of the general formula: ^ C00R2 - 6 carbon atoms, preferably a methyl or ethyl group. Suitable compounds of formula V include diethyl ethoxyraethylenemalonate and dimethyl methoxymothylene-malonate. Reaction nay be effected in the absence or presence of a suitable solvent such as a lower alkanol, e.g. ethanol, at laboratory temperature or with gentle heating. The reaction product of formula III may, if desired, bo separated by filtration or concentration of the reaction medium and, if desired, purified by crystallisation from a suitable solvent, e.g. ethanol or benzene; (ii) by treatment of a formaraidino of the general formula: (wherein and are as hereinbeforo defined) with an alkyl orthoforniate and an alkyl nalonate, e.g. by the method of L. Levai et ol, J. Org. Che ., 1966, 31, 4003.

The fomanii dines of formula VI may be prepared from an aniline of formula IV by treatment with an alkyl orthoforniate , e.g. by the method of C.C. Price et al, J. /oner. Chem. Soc, 1946, 68, 1251.

According to a further feature of the present invention, the compounds of formula II are prepared by the replacement by known methods of a labile atom or group Λ in quinoline compounds of the general formula: (wherein R, ore as hereinbefore defined and A represents an atom or group readily replaceable by a hydroxy 1 group, such as a halogen atom, an amino or mercapto group, an alkoxy, alkylthio or an alkanesulphonyl group of 1 to 6 carbon atoms, or a sulphonic acid group) by a hydroxy 1 group. oxychloride. The resultant 4-chloro compound is then hydrolysed, e.gi'by contacting with an acid medium, to give the required compound of formula II, for example by boiling in acetic acid solution buffered with sodium acetate.

The intermediate 4-chloro compound of formula VII may, if desired, be separated before hydrolysis, by known methods, from the reaction mixture in which it has been prepared or, alternatively, hydrolysed without being isolat after removal of excess phosphorus oxychloride. When the symbol A in formul VII represents e mercapto or alkylthio group, replacement of A by a hydroxyl group is preferably effected by contacting the coDipound of formula VII with an acid medium, e.g. aqueous acetic acid, in the presence of an oxidising agent, e.g. hydrogen poroxide.

The compounds of formula VII wherein A represents a halogen atom may also be prepared by reacting compounds of the general formula: wherein R and R^ are as hereinbefore defined and X represents a halogen (preferably chlorine) atom, with alcohols of the formula Rg H, wherein .R^ is as hereinbefore defined.

The compounds of formula VIII may be prepared from quinoline-3-carboxylic- acid compounds of the general formula: wherein R and R^ are as hereinbefore defined, by known methods for the conversion of hydroxy carboxylic acids into the corresponding halogeno acid halidos, for example by treatment with c phosphorus halide e.g. phosphorus oxychlorido. aqueous alcoholic solution, for example in aqueous ethanol, and recovering the acid of formula IX by acidification of the solution formed; (ii) by the hydrolysis of a corresponding nitrile of the general formula: wherein R and R^ are as hereinbefore defined, e.g. with alkali or acid by the method of C.C. Price et l^, J. /uer. Chera. 5oc., 1946 , 68, 1251· The nitrile of fornula X nay be obtained by the cyclisation of an a-cyano-β-anilinoacrylate of the general formula: wherein R, R and are as hereinbefore defined. Cyclisation is preferably Jl tit effected by heating the conpound of. formula XI at elevated temperature, for example from l80 to 20°C., and more particularly at from 200-280°C,, in a suitable high boiling point solvent, for example a mineral oil, "Dowthorm" or "Diphyl".

The derivatives of formula XI nay be prepared by reaction of an aniline of formula IV with an alkyl orthofornate and an alkyl cyanoacetate, e.g. by the method of R.H. 3aker et al, . /oner. Chen. 3oc», 19 9, 2it 3θ6θ, or by reaction of an aniline of fornula IV v/ith an alkyl alkoxynethylene cyanoacetate, e.g. by the method of C.C. Price et al, J. ;¾ner. Chem. Soc., 1946, 68^ 1251.

According to yet a further feature of the present invention, the compounds of formula II are prepared by reaction of compounds of formula IX with alcohols of formula R CH, wherein R is as hereinbefore defined.

Reaction is preferably effected in the presence of a catalyst such as sulphuric -I or diethyl ether. #' .According to a sti ll further feature of the present invontion, the compounds of formula II are obtained by the transesterif ication by known tnethods of 3-position esters of compounds of formula IXj for example esters wherein the hydrocarbon residue of the ester group is an alkyl group , preferably containing from 1 to 6 carbon atoms , an aralkyl group , e .g. benzyl , or an aryl group , e .g. phenyl . Preferably the 3-po3ition ester of a compound of formula IX used as starting material is another compound of formula I I . Transesterification may be effected by treating the 3-position ester of a compound of formula IX with the appropriate alcohol R 0H , wherein is as hereinbefore defined and has a value di ffering from that of the hydrocarbon residue of the ester moiety of the ester starting materi al , in the presence of a catalyst such as sulphuric aci d , hydrogen chloride or boron trifluoride , the last named being convenie tly used in the form of a complex, such as that formed v/ith dimethyl or diethyl ether.

According to another feature of the present invention, compounds of formula II are prepared by alkylation of the hydro.:y grouiJ in the 7-position of quinoline compounds of the general formula : (wherein R and R are as hereinbefore defined) with a reactive ester of the formula RjX^ (wherein is a halogen atom or the acid residue of a reactive ester such as toluene-£-sulphonate, and R^ is as hereinbefore defined) .

The derivatives of formula XII may be prepared by hydrolysis of an acyl derivative of the general formulai OH (wherein R and Rg are as hereinbefore defined and R^ represents an alkyl group of 1 to 6 carbon atoms, an aralkyl group of 7 to 10 carbon atoms or an aryl group of 6 to 10 carbon atoms), for example by treatment with an alkali metal bicarbonate in a lower aliphatic alcohol.

The quinolines of formula XIII are themselves obtained by cyclisation of an aniline derivative of the general formula: (wherein R, Rg and R^ are as hereinbefore defined), preferably by heating at an elevated temperature, for example from l80-350OCj and more particularly at from 200-280°C, in a suitable high boiling point solvent, for example a mineral oil, "Dowtherm" or "Diphyl".

The aniline derivatives of formula XIV are obtained by known methods by reaction of an aniline of the general formula: (wherein R and R^ are as hereinbefore defined) with a dialkyl alkoxy-methylenemalonate of the general formula V, According to yet another feature of the present invention, compounds of formula II are prepared by reduction by known methods of compounds of the general formula: wherein R ■, Rc and R represent respectively either the groups R, R and -· 7 i R or unsaturated hydrocarbon groups convertible into them by reduction 2 (e.g. allyl), such that at least one of the groups R,_, R^ and R^ is an unsaturated hydrocarbon group as defined above. The reduction may be carried out by known methods, for example by treatment with hydrogen in an inert solvent, e.g. acetic acid or ethanol, in the presence of a suitable hydrogenation catalyst, for example palladium on charcoal.

Compounds of formula XVI where one or both of the groups R and R6 represent unsaturated hydrocarbon groups may be prepared by application of methods already described for compounds of the formula II, for example from an anilinoraethylenemalonate derivative of the general formula: wherein R^, R^ and R^ are as hereinbefore defined, one or both of R^ and Rg representing an unsaturated hydrocarbon group. Compounds of formula XVII are themselves obtained by application of methods already described for analogous compounds of formula III utilizing an aniline of the general formula: XVIII Compounds of formula XVI where represents an unsaturated^hydro-carbon group may be prepared by application of methods hereinbefore described for compounds of the general formula II, more especially by esterification of acids of the general formula: OH wherein R_ and R, are as hereinbefore defined. o Compounds of formula XIX are obtained by application of methods already described for compounds of formula IX.

Salts of the compounds of formula II with bases, g, alkali metal salts, may be obtained by known methods, for example by treatment of a compound of formula II in solution or suspension in a suitable solvent, e.g. dimethyl- formamide, with an equivalent or excess quantity of a base, e.g. an alkali metal hydroxide or hydride, for example sodium or potassium hydroxide or sodium hydride and recovery of the salt by filtration or evaporation of the solvent.

By the term "known methods" in the present specification is meant methods heretofore used or described in the literature.

The quinoline derivatives represented by general formula II may also exist in the tautomeric forms of the general formula: (wherein R, R^ and are as hereinbefore defined), and it is to be understood that the present invention includes within its scope both tautomeric forms.

For purposes of convenience, however, the compounds are described in the present specification and claims in terms of the structural form depicted in formula The following Examples illustrate the preparation of compounds according to the present invention.

EXAMPLE I l-(2-Methoxy-4-nitrophenoxy)-n-octane (13.0 g.) in ethyl acetate (65 ml.) was catalytically reduced with hydrogen in the presence of 5% palladium on charcoal (1.3 g.) at atmospheric pressure and room temperature. The solution obtained after the theoretical hydrogen absorption had occurred, containing l-(4-amino-2-rnethoxyphenoxy)-n~octane , was filtered, treated with diethyl ethoxymethylenemalonate ( 10.5 g.) and the mixture evaporated to dryness on a steam bath in vacuo. The product, diethyl 3-niethoxy-4-n-octyloxyanilinomethylenemalonate , crystallised (ra.p. 48-50°C.) and was dissolved in 'Dowtherm A' (130 ml.) and the solution heated in a Woods metal bath at 260-270°C. for 1 hour. The cooled solution was diluted with light petroleum (b.p. 60-80°C.) and the crude product filtered off and dried.

Recrystallisation by dissolving in boiling acetic acid (50 ml.), filtering whilst hot and precipitating the product by the addition of boiling methanol (100 ml.) gave ethyl 4-hydroxy-7-methoxy-6-n-octyloxyquinoline-3-carboxylate (4.95 g.), m.p. 256-258°C.

The l- (2-methoxy-4-nitrophenoxy)-n-octane used as starting material in the above preparation was prepared according to the method of R.F. Collins and M. Davis. J. Chem. Soc. 196l , 1863 , as followe:- Potassium p_-nitroguaiacoxide (103.6 g.) in dimethylformamide (515 nil.) was treated with n-octyl bromide (95 ml.), heated with stirring on a steam-bath for 1 hour, poured into water and the product filtered off.

Crystallisation from methanol (500 ml.) gave l-( 2-methoxy-4-nitrophenoxy)-n-octane (ll6 g.), m.p. 36.5-38°C.

Proceeding in a similar manner to that described above for the preparation of ethyl 4-hydroxy-7-ciethoxy-6-n-octyloxyquinoline-3-carboxylate but replacing the 1- (4-amino-2-methoxyphenoxy)-n-octane by the appropriate aminophenoxyalkane derivative obtained by the reduction of the corresponding nitrophenoxyalkane , itself prepared by the method of J f following compounds were obtained ethyl 6-n-heptyloxy-4-hydroxy-7-methoxyquinoline«-3-carboxylate , m.p. 256-259°C. (from l- (2-methoxy-4-nitrophenoxy)-n-heptane , m.p. 53-55°C); ethyl 7-ethoxy-4-hydroxy-6-n-octyloxyquinoline-3-carboxylate m.p. 250-251°C. (from l- ( 2-ethoxy-4-nitrophenoxy )-n-octane , m.p. 49-50°C,); ethyl 4-hydroxy-7-methoxy-6-n-nonyloxyquinoline-3-carboxylate , m.p. 258-260°C. (from 1- (2-methoxy-4-nitrophenoxy)-n-nonane , m.p. 47.5-49°C.); ethyl 6-n-decyloxy-4-hydroxy-7-methoxyquinoline-3-carboxylate , m.p. 250-252°C. (from l- (2-methoxy-4-nitrophenoxy)-n-decane, m.p. 49-50°C); ethyl 4-hydroxy-7-raethoxy-6-n-undecyloxyquinoline-3-carboxylate , ra.p. 252-254°C. (from l-(2-methoxy-4-nitrophenoxy)-n-undecane , m.p. 51-52.5°C. ) 5 ethyl 4-hydroxy-7-isobutoxy-6-n-octyloxyquinoline-3-carboxylate, m.p. 257-259°C. (from l- ( 2-isobutoxy-4-nitrophenoxy)-n-octane, o m.p. 52-53 C., itself prepared from 2-isobutoxy-4-nitrophenol , an oil, which was obtained from 3 , 4-di-isobutoxy-nitrobenzene by the method of R.F. Collins and M. Davis, J. Chem. Soc., 1961 , 1863 ) ; ethyl 6-n-decyloxy-7-ethoxy-4-hydroxyquinoline-3-carboxylate , m.p, 244-246°C. (from l- (2-ethoxy-4-nitrophenoxy)-n-decane . m.p. 57.5-59°C.), and ethyl 6-n-decyloxy-4-hydroxy-7-isopropoxyquinoline~-3-carboxylate , m.p. 194-196°C. (from l-(2-isopropoxy-4-nitrophenoxy)-n-decane , m.p. 45.5-47.5°C.) EXAMPLE II Proceeding as described in Example I, l- (2-ethoxy-4-nitrophenoxy)-n-dec¾ne (10.2 g.) was reduced and the l- (4-amino-2-ethoxyphenoxy)-n-decane and cyclised in boiling 'Dowtherra A1 to give crude ethyl 6-n-decyloxy-7-ethoxy-4-hydroxyquinoline-3-carboxylate (7.1 g.). A sample, recrystallised from acetic acid and methanol, as described in Example I, melted at 244-246°C.

The l-(2-ethoxy-4-nitrophenoxy)-n-decane used as starting material in the above preparation was prepared as follows :- 4-Nitrocatechol mono-sodium salt (17.2 g.) was dissolved in dimethylforrnamide (l80 ml.) and n-decyl bromide (22.1 g.) was added.

The mixture was stirred and heated on a steam-bath for 1 hour and poured into water (1 litre). The precipitated solid was filtered off and dissolved in the minimum of boiling methanol. The solution was treated with sodium hydroxide solution (7.0 ml., 50% w/w) and diluted with water (500 ml.). The mixture was clarified with charcoal and filtered. The filtrate was acidified with concentrated hydrochloric acid (15 ml.) and the precipitated oil extracted with diethyl ether. The extracts were washed with water, dried over anhydrous sodium sulphate and evaporated and the residue recrystallised from light petroleum (b.p. 40-60°C.) to give l-(2-hydroxy-4-nitrophenoxy )-n-decane (11.3 g.), m.p. 46-49 °C. l-(2-Hydroxy-4-nitrophenoxy)-n-decane (10.8 g.) was dissolved in dimethylforrnamide (50 ml .) and the solution treated with sodium hydride (1.95 g»t 50% suspension in oil). The mixture was heated on the steam-bath for 5 minutes, then treated with ethyl toluene -p_-sulphonate (8.0 g.) dissolved in dimethylforrnamide (50 ml.). After heating for a further 1 hour, the mixture was poured into ice-cold water (500 ml.), made alkaline with sodium hydroxide solution, and the solid product filtered off.

Crystallisation from methanol gave l-(2-ethoxy-4-nitrophenoxy)-n-decane (10.7 g.)| m.p. 50-55 C. sample, recrystallised from methanol,, melted at 53-55°C.

The following compounds were prepared in a similar manner (a) ethyl 4-hydroxyr6-n-octyloxy-7-n-propoxyquinoline-3-carboxylate , m.p. 252-254°C;, from 1- (2-n-propoxy-4-nitrophenoxy)-n-octane , The l- (2-hydroxy-4-nitrophenoxy)-n-octane was prepared by the procedure described above from 4-nitrocatechol mono-sodium salt and n-octyl bromide · ethyl 4-hydroxy-7-isopropoxy-6-n-octyloxyquinoline-3-carboxylate , m.p. 215-217°C., from l- (2-isopropoxy-4-nitrophenoxy)-n-octane, m.p. 43-44°C., itself prepared from l- (2-hydroxy-4-nitrophenoxy)-n-octane and isopropyl bromide, ethyl 4-hydroxy-7-isopropoxy-6-n-nonyloxyquinoline-3-carboxylate , m.p. 203-205°C, from l- ( 2-isopropoxy-4-nitrophenoxy)-n-nonaner m.p. 43-45°C . , itself prepared from l-(2-hydroxy-4-nitrophenoxy)-n-nonane , m.p. 42-45°C., and isopropyl bromide. The l-(2-hydroxy-4-nitrophenoxy)-n-nonane was prepared by the procedure described above from 4-nitrocatechol mono-sodium salt and n-nonyl bromide, ethyl 7-ethoxy-4-hydroxy-6-n-nonyloxyquinoline-3-carboxylate , m.p. 243-245°C . , from l-(2-ethoxy-4-nitrophenox )-n-nonane , m.p. 40-42°C . , itself prepared from l- ( 2-hydroxy-4-nitrophenoxy)-n-nonane, m.p. 42-45°C., and ethyl toluene-p_-sulphonate . The l- (2-hydroxy-4-nitrophenoxy)-n-nonane was prepared by the procedure described above in (c) . ethyl 7-n-butoxy-6-n-decyloxy-4-hydroxyquinoline-3-carboxylate , m.p. 239-242°C , from l-(2-n-butoxy-4-nitrophenoxy)-n-decane , m.p. 35-37°C., itself prepared from l- ( 2-hydroxy-4-nitrophenoxy)-n-decane, m.p, 46-48°C., and n-butyl iodide. The l- (2-hydroxy-4-nitrophenoxy)-n-decane was prepared by the procedure described above . ethyl 7-ethoxy-6-n-heptyloxy-4-hydroxyquinoline-3-carboxylate , m.p. 252-253°C., from l- ( 2-ethoxy-4-nitrophenoxy)-n-heptane . m.p, 36-38°C., itself prepared from l- (2-hydroxy-4-nitrophenoxy)-n-heptane, m.p. 43-45°C., and ethyl toluene-p_-sulphonate . The l-(2-hydroxy-4-nitrophenoxy)-n-heptane was prepared by the procedure described above from 4-nitrocatechol mono-sodium salt and n-heptyl m.p. 177-179 C., from l-(2-sec.-butoxy-4-nitrophenoxy)-n-decane , m.p. 33-36°C., itself prepared from l-(2-hydroxy-4-nitrophenoxy)- n-decane and sec. -butyl bromide. The l-(2-hydroxy-4-nitrophenoxy)- n-decane was prepared as described above. (h) ethyl 7-ethoxy-4-hydroxy-6-n-undecyloxyquinoline-3-carboxylate , m.p. 239-24l°C., from l-(2-ethoxy-4-nitrophenoxy)-n-undecane , m.p. 48-50°C, itself prepared from l-(2-hydroxy-4-nitrophenoxy)-n- undecane, m.p. 42-44°C, and ethyl toluene-£-sulphonate . The l-(2- hydroxy-4-nitrophenoxy)-n-undecane was prepared by the procedure described above from 4-nitrocatechol mono-sodium salt. and n-undecyl bromide . (i ) ethyl 6-n-decyloxy-4-hydroxy-7-n-propoxyquinoline-3-carboxylate , m.p. 244-245°C, from l-(4-nitro-2-n-propoxyphenoxy) -n-decane, m.p. 59-6l°C., itself prepared from l-(2-hydroxy-4-nitrophenoxy)- n-decane and n-propyl bromide. The l-(2-hydroxy-4-nitrophenoxy)-n- decane was prepared as described above.

EXAMPLE III ' l-(2- ethoxy~4-nitrophenoxy)-n-decane (154 g.; prepared as described in Example I) was reduced with hydrogen in ethyl acetate (l litre) in the presence of 5% palladium on charcoal catalyst at atmospheric pressure and room temperature to 1 -(4-aminor-2-methoxyphenoxy) -n-decane . The solution was filtered, treated with diethyl ethoxymethylenemalonate (108 g.) and evaporated under reduced pressure to give diethyl 4-n-decyloxy-3-methoxy-anilinomethylenemalonate , m.p. 68°C. This solid was dissolved in phos-phorus oxychloride (200 ml.) and heated on the steam-bath for 3 hours.

The excess of phosphorus oxychloride was evaporated in vacuo and the residue dissolved in glacial acetic acid (2 litres). The solution was treated with anhydrous sodium acetate (200 g.), heated under reflux, with stirring, for 6 hours and poured into ice-cold water (12 litres). The precipitated solid was filtered off, washed with water and ethanol and dried o -at about 90 C. to give ethyl 6-n-decyloxy-4-hydroxy-7-methoxyquinoline-3- methanol as described in Example I, melted at 252-256°C.

The following compound was prepared in a similar manner :-ethyl 6-n-decyloxy-4-hydroxy-7-isopropoxyquinoline-3-carboxylate, m.p. 19 -196°C, from l-(2-isopropoxy-4-nitrophenoxy)-n-decane, m.p. 45.5-^7.5°C., itself prepared by the method described in Example I from l-(2-hydroxy-4-nitrophenoxy)-n-decane and isopropyl bromide.

EXAMPLE IV Ethyl 6-n-decyloxy-7-ethoxy-4-hydroxyquinoline-3-carboxylate (50 g.j prepared as described in Example I) was refluxed in ethanol (500 ml.) and water (500 ml.) containing sodium hydroxide (50 g.) for 1 hour. The solution obtained was diluted with water until just turbid, and filtered hot through Hyflo Supercel. Acidification of the filtrate with concentrated hydrochloric acid gave 6-n-decyloxy-7-ethoxy-4-hydroxyquinoline-3-carboxylic acid (48 g.), m.p. 260-262°C, raised by recrystallisation from dimethyl-formamide to 263-264°C. This acid (65 g.) was suspended in methanol (1.4 litres), treated with boron tri fluoride -diethyl ether complex (65 ml.) and the mixture refluxed and stirred for 1.5 hours. The solution was added to ice-cold water (5 litres) and the solid obtained filtered off, washed with water and recrystallised by dissolving in boiling acetic acid, filtering whilst hot and precipitating the product by the addition of boiling methanol to give methyl 6-n-decyloxy-7-ethoxy-4-hydroxyquinoline-3-carboxylate (51 g.), m.p. 247-249°C.

The following compounds were prepared in a similar manner starting with the corresponding ethyl esters (prepared as described in Examples I and II):- methyl 7-ethoxy-4-hydroxy-6-n-octyloxyquinoline-3-carboxylate , m.p. 251-253°C.j methyl 4-hydroxy-7-isopropoxy-6-n-octyloxyquinoline-3- o carboxylate, m.p. 239-241 C.; n-propyl 4-hydroxy-7-methoxy-6-n-octyloxyquinoline-3-carboxylate , m.p. 232-234°C; methyl 7~ethoxy-4-hydroxy-6-n-nonyloxyquinoline-3-carboxylate , n.p. 2 7-2 9 °C; methyl 4-hydro:-y-7-isopropo.:y-6-n-nonylo yquinoline-3-carboxylate , n.p. 222-225°C.; methyl 6-n-dec3''lo:cy-4-hydro:or-7-raetho-¾rquinoline-3-carbo2-ylate , n.p. 237-239°C.; methyl 4-hydroxy-7-raethoxy-6-n-octylo.iyquinoline-3-carboxylate, m.p. 247-249°C; methyl 7-etho-_y-6-n-heptylo:cy-4-hydroxyquinoline-3-carboxylate, m.p. 257-259°C.; methyl 7-ethoxy-4-hydroxy-6 -n-undecy 1 oxyqui nol i ne-3-c arbo;cy lat e , ra.p. 249-250°C.; and methyl 6-n-decyloxy-4-hydroxy-7-isopropoxyquinoline-3-carbo3ylate, m.p. 225-227°C.

' EX/jMPLS V 6-n-Docyloxy~7-ethoxy-4-hydroxyquinoline-3-carboxylic acid (5*6 g; prepared as described in Example IV) was heated under reflux in phosphorus oxychloride (56 ml) for one hour. The excess of phosphorus oxychloride was removed by evaporation under reduced pressure and the residue containing 4-chloro-6-n-decyloxy-7-etho2:yquinoline-3-carbonyl chloride was refluxed for 15 minutes with n-propanol (56 ml). The excess of propanol was removed by evaporation, the residue dissolved in acetic acid (56 ml) and treated with sodium acetate (5.6 g.). The solution was refluxed for 2.25 hours and then poured into water (400 :r.l). The solid obtained was filtered off, dried, and crystallised from dimethyl formami do, giving n-propyl 6-n-dccyloxy-7-cthoxy-4-hydroxyquinolino-3-carboxylatc (4.4 g) , m.p. 205-207°C.

The following compounds were prepared in a similar manner starting with the corresponding carboxylic acid (proparod as described in Example IV) and propan-2-ol: isopropyl 7-n-butoxy-6-n-decyloxy-4-hydroxyquinolino-3-carboxylato , m.p. 213-215°C, and EXAMPLE VI Diethyl 4-n-dccyloxy-3-othoxyanilinomethylenemalonatc (5·0 g» prepared as described in Example II) and phosphorus oxychlorido (4.4 ml) wore heated together on the steam-bath for 3 hours. The excess phosphorus oxychloride was evaporated under reduced pressure, the residue dissolved in methanol (20 ml) and the solution poured into ice-cold water (100 nl). The mixture was neutralised with sodium hydroxide solution, the precipitate filtered off, washed with water, dried and recryst llisod from light petroleum (b.p. 60-80°C) to give ethyl 4-chloro-6-n-decyloxy-7-ethoxyquinoline-3~ carboxylato, a. . 82*5-83·5°0· This ester (3.0 g) was" heated under reflux for one hour in glacial acetic acid' (30 ml) containing anhydrous sodium acetate (6.0 g) and the mixture poured into water (100 ml). The product was filtered off and recrystallisod from acetic acid and methanol, as described in Example I, to yield ethyl 6-n-decyloxy-7-ethoxy-4-hydroxyquinolino-3-carboxylatc, m.p. 24l-244°C. identical with the product described in Exa:nplc I.

Similarly prepared was ethyl 4-hydroxy-7-methoxy-6-n-octyloxy-quinolino-3-carboxylato n.p. 258-260°C.

EXAMPLE VII Λ solution of ethyl 6-n-decyloxy-7-othoxy-4-hydroxyquinolinc-3-carboxylate (8.3g; prepared as described in Example I) in mothanol (300 ml) and concentrated sulphuric acid (10 ml) was heated under reflux for 12 hours, then concentrated in vacuo and poured into ice-water. The precipitate was filtered off, washed v/ith wator, dried and rocrystallised from dimethyl-formamide, giving methyl 6-n-dccyloxy-7-cthoxy~4-hydroxyquinoline-3-carboxylato , m.p. 245-248°C, not depressed by a specimen prepared as in Example IV.

The following compound was prepared in a similar manner, but using n-propanol in place of methanol : n-propyl 6-n-decyloxy-7-othoxy-4-hydroxyquinolino-3-carboxylatc , m.p. 203-206°C.

EXAMPLE VIII peroxide (1 ,2 ml , 30%) in acetic acid (10 ml ) . The solution was heated on the steam-bath for 2 hours , treated with a further quantity of hydrogen peroxide (1.2 ml ) , and heated for a further 2 hours . ¾o solution was diluted with water and the product extracted with chloroform. Evaporation of the washed and dried extracts gave a soli d v/hich was triturated with ethanol , and recrystcllised twice from acetic acid to yield ethyl 6-n-docyloxy-7-cthoxy-4-hydroxyquinoline-3~carboxylate , m.p . 235-238°C , undepressed by an authentic sample prepared as described in Example I and having identical characteristi cs by thin-layer chromatography .

The mercapto compound employed as starting materi al was obtained as follows : A solution of sodium (1.01 g ) in dry ethanol (l80 ml ) was saturated with hydrogen sulphide . Ethyl 4-chloro~6-decyloxy-7-othoxyquinoline-3-carboxylato (17 ·5 g » ns.p . 82«5-83.5°C ) , prepared as described in Example 71 , was added to the solution, v/hich was heated under reflux for 1 hour, poured into water and acidified v/ith hydrochloric aci d. The product was extracted with chloroform. The washed and dried extract was evaporated and ethyl 6-n-decyloxy-7-ethoxy-4-mercnptoquinoline-3-carboxylato crystallised from ethanol as an orange solid (10.0 m.p. 203-206°C . A sample rccrystallisod o o from methanol had m.p . 200 C , resoli d fying and m.p. 241 C.

EXAMPLE IX Λ solution of ethyl 6-n-docyloxy-7-ethoxy-4-methylmercaptoquinolinc~ 3-carboxylate (2 g ) in acetic acid ( 20 ml ) was treated with hydrogen peroxide ( 1.04 ml , 30%) and heated on the stea -b^th for 16 hours . The solution v/as cooled and the solid filtered off and recrystallised from acetic acid. The product had a m.p. of 235-238°C , undepressed by an authentic sample of ethyl 6-n-decyloxy-7-etho:.y-4-hydroxyquinoline-3-carboxylate prepared as described in Example I , and identical v/ith it by thin-layor chromatography.

The 4-methylmercapto compound used as starting material was prepared as follows : Ethyl 6-n-decyloxy-7-ethoxy-4-mercaptoquinoline-3-carboxylate and, after evolution of hydrogen had ceased, with methyl iodide (0.37 ml).

The solution was heated on the steam-bath for 1 hour and poured into water. The solid product was recrystollised fron methanol to give ethyl 6-n-decyloxy-7-ethoxy-4-methylmcrcc.ptoQuinolino-3-carboxylate as a. cream solid (1.4 g), m.p. 82-83°C.

SX/MPLS X Bis-(3-ethoxy-4-n-decyloxyphcnyl )f orma idine (l4 g) , diethyl malonato (10 g), ethyl orthofortnate (2 g) and ammonium chloride (0,25 g) j were heated together under nitrogen at 125-130°C (both temperature ) for 2 hours. further portion of ethyl orthofortnate (2 g) v/as added end the nixturo was heated for 1 hour. The cthanol present v/as then allowed to distill from the mixture while heating v/as continued for a further 6 hours. The mixture v/as cooled and diluted with benzene (100 ml), hydrochloric acid (ca. 10 nl of a 30% solution) was added, and the benzene layer was washed v/ith water (3 x 10 ml), dried and evaporated. The residual oil v/as refluxed in "Dowtherm1' (50 ml) for 30 minutes and the solution v/as poured into light petroleum (b.p. 100-120°C, 500 ml). The gelatinous solid v/as centrifugod off and mixed v/ith glacial acetic acid (ca.30 ml). Centrifuging of this mixture gave an oily solid which v/as crystallised from glacial acetic acid to give ethyl 6-n-decyloxy-7-etho--y-4-hydroxyquinoline— 3-carboxylate , m.p. 244-245«5°C, identical with a sample prepared as in Example I.

The bis-(3-othoxy-4-n-docyloxyphonyl )formamidine v/as obtained as follows : l-(4-/tmino-2-ethoxyphenoxy)-n-docano, prepared as described in Example II from l-(2-ethoxy-4-nitrophenoxy)-n-decane (64.6 g), was refluxed for 2½ hours with ethyl orthoformate (15 ml) (bath temperature l45°C). The othanol produced in the reaction was distilled off, and the product diluted with an equal volume of light petroleum (b.p. 80-100°C), then cooled, yielding a solid (48 g, m.p. 61.5-63 ·5°θ). Rccry3tallisation gave bis-(3~ othoxy-4-n-decyloxyphenyl )formamidine (42.5 g), m.p. 62«5~64.5°C.

SX JMPLS XI and water (5 nil) were added and the mixture boiled under reflux for '4 hours. After cooling, the mixture was diluted with water, and acidified with 2N hydrochloric acid. The solid was collected and recrystallised from ethanol to give unchanged starting material, m.p, 315-3l8°C. After standing overnight, the ethanol liquors deposited a pale crean solid, m.p. 240-255°C (deconp.), which v/as recrystallised from ethanol to give 6-n-decyloxy-7-ethoxy-4-hydroxy-quinoline-3~carboxylic acid, m.p. 259-264°C (decomp.), which was converted into its ethyl ester by the method of Example IV".

The 3-cyano-6-n-decylo:cy-7-othoxy-4-hydroxyquinoline was prepared, as follows: 4-n-Decyloxy-3-ethoxynitrobenzene (25 g) in methanol (175 nil) was catalytically reduced and the solution v/as evaporated at atmospheric pressure under nitrogen. To the residue was added ethyl orthofornate (11.5 g) and ethyl cyanoacetatc (17 ·5 g), and the mixture was stirred and heated at l65°C. until almost the theoretical amount of ethanol had distilled out (2 hours). The residue v/as cooled and recryst llised once from methanol and twice from cyclohex ne giving ethyl a-cyano^-(4-n-dccyloxy-3-Gthoxyanilino)acrylate, m.p. 105-107°C. This ester (15 g) was added to gently rofluxing "Dowthcrra" (75 ml), and refluxed with stirring for 4 hours, using a short air condenser so that the ethanol formed in the reaction could escape. The mixture was allowed to cool and v/as diluted with light petroleum (b.p. 40-60°C). The brown solid v/as collected and recryst llised from dimethylfor amide to give 3-cyano-6-n-decylo.¾r-7-othoxy-4-hydro:-yquinolino , m.p. 325-327°C.

EXAMPLE XII Ethyl 6-n-decyloxy-4,7-dihydroxyquinoline-3-cnrboxylate (377 nig) and sodium hydride (58 rag, 50c0 w/w in oil) were warmed together in dimethyl-formamide (5 ml.). Ethyl toluene-£-sulphonate (200 g) was added and the mixture was heated under reflux for 1 hour, and poured into water. The precipitate was filtered off, washed with water, dried and crystallised from o ethanol givxng a colourless solid, m.p. 232-9 C. Recrystallisation from methanol gave ethyl 6-n-decyloxy-7-othoxy-4-hydroxyquinoline-3-carboxylate , was prepared as follows: l-(2-Hydro.cy-4-nitrophenoxy)-n-decano, prepared as described in Example II, was acetylated with acetic anhydride and pyridine. The product, 3-acetoxy-4-n-decylcxynitrobonzene (6,87 g), in ethyl acetate (50 ml) was hydrogenated over 5% Pd-charcoal (0,85 g) at 40°C and normal pressure. After reduction was complete, the catalyst was removed and the filtrate was taken to dryness in vacuo giving the amine (6.25 g). This was treated with diethyl ethoxymethylenemalonate (4.9 g) and the mixture was heated on the steam-bath for 10 minutes before it v/as slowly poured into boiling "Diphyl" (120 nl).

The mixture was allowed to boil for 20 minutes after the addition was conplete and was then cooled rapidly to roon temperature. The product was filtered off, washed with light petroleum and crystallised from dimethylformaiiu.de giving ethyl 7-acctoxy-6-n-decyloxy~4-hydroxyquinoline-3-carboxylate , m«pi 240-.242°C. This product (0.45 g) and potassium bicarbonate (0.11 g) were heated together under reflux in methanol (100 ml) and water (10 ml) for 30 minutes. The solvent v/as removed in vacuo, water v/as added, the precipitated product was filtered off, washed with water and crystallised from methanol, giving ethyl 6-n-dccylcxy-4,7-dihydroxyquinoline-3-carboxylate, m.p. 2l4-2l6°C, EXAMPLE XIII Ethyl 7-allyloxy-6-n-decyloxy-4-hydroxyquinolinc-3-carboxylate (0.86 g) in glacial acetic acid (100 ml) was hydrogencted over 5% Pd-charcoal (0.3 g) at 60-65°C and normal pressure. After one mole of hydrogen had been taken up the catalyst v/as filtered off and the filtrate was evaporated to dryness in vacuo. The residue was triturated with ethanol giving ethyl 6-n-decyloxy-4-hydroxy-7-n-propojcyquinoline-3-carboxylat , tn.p. 240-242°C, undepressed by a sample prepared as in Example II.

The 7-allyloxyquinoline derivative used as starting material v/as obtained by the method of Example III from 1- (2-ellyloxy-4-nitrophenoxy )-n-decane, m.p. 36-38°C, itself prepared by the method of Example II from 1-(2-hydro:cy-4^nitropheno:cy)-n-decane and allyl bromide.

EXAMPLE XIV giving n-propyl 6-n-decyloxy-7-ethoj.y- -hydroxyquinoline-3-carboxylate , o m.p. 199-201 C , undepressed by an authentic specimen prepared as described in Exanjple V.

The allyl ester used in this preparation was obtained by the method of Example V from 6-n-decyloxy-7-ethoxy-4- hydroxyquinoline-3-carboxylic acid and allyl alcohol .

EX/MPLE XV Ethyl 6-n-decyloxy-7-etho,.y-4-hydroxyquinoline-3-carboxylate (10.0 g$ prepared as described in Example I ) suspended in diraethylf ormarai de (lOO lnl ) was treated with sodiuni hydride (50% suspension in mineral oil , 1.26 g ) and stirred with gentle warning on r steara-bath for 10 minutes , givin a solution of the sodium salt of ethyl 6-n-decyloxy-7-etho::y-4-hydroxy-quinoline-3-carboxylate .

EX/iMPLE XVI A mixture of othyl 6-n-decyloxy-7-ethoxy-4-hydroxyquinoline-3-carboxylate (4.17 g ; prepared as in Example I ) ,, potassium hydroxide (Ο.56 g ) and othnnol (200 nl ) was warned on a stcan-bath until a clear solution was obtained. The solution was then cooled to laboratory temperature and clarified with "Hyflo Supercel " to give n clear solution containing the potassiun salt of othyl 6-n-decyloxy-7-othoxy-4-hydroxyquinoline-3-carboxylat According to a further, feature of the present invention, there are provided compositions suitable for administration to chickens to prevent coccidiosis, including concentrates for addition to chicken feedstuff or drinking water, comprising, as a coccidiostat , at least one quinoline derivative of formula II, or non-toxic salt thereof, in association with a physiologically innocuous carrier. By the expression physiologically innocuous carrier1 as used herein is meant a carrier which is not harmful to the chicken. The carrier may be a solid or semi-solid or a liquid, uch compositions are conveniently produced by intimately dispersing the active ingredient through the carrier, if necessary, where the carrier is a liquid in which the active substance is but sparingly soluble, e.g. water, using an emulsifying, dispersing, suspending or wetting agent.

Preferred compositions are solids or semi-solids in which the carrier is provided at least in part by a chicken feedstuff, i.e. an organic or mineral substance which is intended to be fed to the chicken; that is to say, the active ingredient' may be incorporated in a solid or semi-solid feedstuff. Incorporation of the active ingredient in the feedstuff, which may be a commercial starter, grower, layer or breeder feed, may be effected by any conventional method such as stirring, tumbling or grinding. Compositions of varying concentrations can be prepared by altering the ratio" of carrier to active ingredient. The active ingredient may also be incorporated in the feedstuff in the form of a powder concentrate containing active ingredient and a solid, physiologically innocuous carrier, e.g. wheat middlings, talc, kaolin or chalk or a diatomaceous earth, such as kiesel-guhr, or a mixture thereof, and such compositions are also included within the scope of this invention. These compositions may also contain agents to promote adhesion of the active ingredient to the carrier, for example soya oil. To the active ingredient or powders containing it, there may be added before admixture with the feedstuff, one or more physiologically innocuous polyoxyethylene (20) sorbitan monooleate. Alternatively, when a wetting, suspending, emulsifying, or dispersing agent is added to the active ingredient or powder, the composition so obtained may be mixed with water to provide stable dispersions suitable for addition to feedstuffs.

Compositions suitable for addition to feedstuffs which comprise the active substance in association with a wetting, suspending, dispersing or emulsifying agent, with or without a physiologically innocuous carrier, are also included within the scope of this invention. The compositions of the invention suitable for the prevention of coccidiosis in chickens, may, if desired, also contain one or more additional prophylactic or therapeutic agents, for example antibacterial agents such as furazolidone, and coccidio-stats such as 2~chloro-i-nitrobenzamide , pyridine-3-sulphonamide, sulpha-quinoxaline or nitrofurazone, though the inclusion of such additional coccidiostats is, in general, neither necessary or desirable. Also they may contain other substances known to be useful in promoting the growth of poultry or their egg production such as, for example, ^-hydroxy-? -nitro-phenylarsonic acid and antibiotics such as penicillin and penicillin derivatives.

Liquid compositions may be dispersions of the active ingredient in drinking water, and these compositions may be prepared from concentrates which may be added to water, or are self-emulsifying with water. Such concentrates comprise the active ingredient in association with a wetting, suspending, dispersing or emulsifying agent, with or without a physiologically innocuous carrier, or in association with a water-soluble physio-logically innocuous carrier, and are included within the scope of this invention. Examples of these concentrates are:- (1) Mixtures of the active ingredient with a wetting or dispersing agent ; (2) Powders comprising the active ingredient, a physiologically innocuous carrier, and a wetting, suspending or dispersing (3) Stable dispersions obtained by mixing concentrates of types (l) or (2) with water; and (*) Mixtures of the active ingredient with a water-soluble physiologically innocuous carrier, e.g. sucrose or glucose.

It is also possible to administer the compounds of the present invention orally to chickens in the form of granules, pellets, suspensions, solutions and emulsions comprising the active quinoline ingredient in association v/ith suitable physiologically innocuous carriers and adjuvants. Such administration is, however, generally less convenient and therefore such compositions are not preferred.

The compositions of the present invention may contain from about 0.0001 to about 90% by weight of one or more of the compounds of formula II. Concentrates for addition to chicken feed generally contain from about 1% to about 90 by weight of one or more of the compounds of formula II, and preferably about -5 by weight absorbed on or mixed with a carrier. As already mentioned, feedstuffs generally contain 0.0001 to 0.05% of the active compound.

The amount of active quinoline compound required for effective prophylactic control of coccidiosis in chickens is very low. Good results have been obtained in the prevention of disease due to E. tenella and E. acervulina by the administration in feed of a quantity of quinoline derivative of formula II equal to about 0,0002% to O.Q5% by weight of the food consumed. Optimum, results are usually obtained by the administration of a quantity of active ingredient equal to about 0,001% to about 0.025%, and particularly 0,001% to 0.00½%, by weight of the food consumed, more especially with the specific compounds of particular value hereinbefore mentioned. Moreover, methyl ^-hydroxy-V-isopropoxy-S-n-octyloxyquinoline-3-carboxylate and ethyl ^-hydroxy-7-isopropoxy-6-n-octyloxyquinoline-3-carbox late have been found to be effective prophylactically against E, tenella and E, acervulina when administered in a quantity equal to 0.001% o J octyloxyquinoline -3-carboxylate , methyl S-n-decyloxy-y-ethoxy-^-hydroxy-quinoline-3-carboxylate and ethyl 6-n-decyloxy-7-ethoxy-^-hydroxyquinoline-3-carboxylate have been found to give effective prophylactic eontrol of these organisms when administered in a quantity equal to 0.0002 - 0,0005 w/w in the feed. Furthermore, the quinoline derivatives of formula II, and more particularly the preferred compounds, are highly active in the prevention of infections caused by other species of Eimeria. including the important species E. necatrix, E, maxima and E. brunetti, when administered in similar concentrations in the feed. For example, ethyl 6-n-decyloxy-7-ethoxy-i-hydroxyquinoline-3-carboxylate has been found to be effective prophylactically in preventing disease caused by E. necatrix when administered in a quantity equal to 0.002$ to 0.00^% w/w in the feed and in preventing disease caused by E. maxima and Ξ. brunetti when administered in a quantity equal to 0.001$ w/w in the feed.

It will be appreciated that when concentrates in the form of pellets or granules are employed as the means for administration of the quinoline derivatives, the proportion of quinoline compound present in the pellets or granules themselves is considerably higher than the above-mentioned proportions suitable in feedstuffs for the effective prophylactic control of coccidiosis, and that the concentrates can be distributed throughout a chicken feedstuff so as to give, on average over the whole of the feed, an amount of 0.0001$ to 0.05$ by weight of the quinoline compound.

Advantageously, the average particle size of the quinoline compound of formula II incorporated in the chicken feedstuff is from about 1 to about 50 microns, and is preferably less than 30 microns.

The following Examples illustrate -compositions according to the present invention; the percentages stated are by weight.

V EXAMPLE XVII Ethyl 6-n-decyloxy-7-ethoxy-if-hydroxyquinoline-3-carboxylate (l8 parts by weight) was added to wheat middlings (82 parts by weight), and intimately mixed. The mixture was incorporated in a feedstuff suitable for chickens to give a final concentration of 0.002% to 0.00 % by weight of quinoline derivative. The treated feedstuff was suitable for feeding to chickens to prevent coccidiosis caused by E. tenella.

E, acervulina. E. necatrix. E. brunetti and E, maxima.

EXAMPLE XVIII Ethyl 7-ethoxy-i-hydroxy-6-n-octyloxyquinoline-3-carboxylate (5 parts by weight) was added to limestone flour (20 parts by weight). The mixture was ground and incorporated in a suitable feedstuff for chickens to give a final concentration of 0, 002% to 0.00¾¾ by weight of quinoline derivative. The treated feedstuff was suitable for feeding to chickens to prevent coccidiosis caused by infections with E. tenella and E. acervulina.

EXAMPLE XIX Soya oil (3 parts by weight) was sprayed onto stirred wheat middlings (88 parts by weight) to achieve a uniform distribution. Ethyl 6-n-decyloxy-7-ethoxy- -hydroxyquinoline-3-carboxylate (9 parts by weight) was then added and intimately mixed. The concentrate thus obtained was suitable for incorporation into a feedstuff for chickens to give a final concentration of 0, 002% to 0.00k% by weight of quinoline derivative. The treated feedstuff was suitable for feeding to chickens to prevent coccidiosis caused by E. tenella. E. acervulina, E. necatrix. E, brunetti and E. maxima.

EXAMPLE XX A composition containing the following ingredients: ethyl 6-n-decyloxy-7-ethoxy-i-hydroxyquinoline-3-carboxylate 3 g. sucrose 92 g. ,1 when- added to drinking water at the rate of 0. 8 g. per litre provided a concentration of 0.00k of active substance in the water .

CXAMPLS XXI Ethyl 6-n-decyloxy-7-ethoxy-i-hydroxyquinoline-3-carboxylate (l g) was ground up with distilled water (5 ml). Tragacanth mucilage (1 .25 ; 3 ml) was added, and the mixture was made up to 10 ml. with distilled water. The final suspension was suitable for oral administration to chickens.

JSXAMPIJS XXII ithyl 6-n-decyloxy-7-ethoxy-i-hydroxyquinoline-3-carboxylate (50 mg) was mixed with Cremaphor .151 ( 0. 1 ml) and a little water, and the mixture was ground to a fine suspension then diluted with water to a total-volume of 5 ml. The final suspension was suitable for oral administration to chickens.

Similar compositions as described in any one of ICxamples XVII to XXII. may be prepared wherein the stated quinoline derivative is replaced by another of the compounds of formula II , or non-toxic salt thereof, more particularly one of the preferred compounds, for example, ethyl if-hydroxy-7-isopropoxy-6-n-octyloxyquinoline-3-carboxylate , methyl if-hydroxy-7-isopropoxy-6-n-octyloxyquinoline-3-carboxylate , methyl 7-ethoxy-i-hydroxy-6-n-octyloxyquinoline-3-carboxylate or methyl 6-n-decyloxy-7-ethoxy-^-hydroxy-quinoline-3-carboxylate.

Tests were carried out to demonstrate the anti-coccidial activity of compounds of the present application and its superiority compaied with that of other compounds within the disclosure of Israel Patent No. 25347. The compounds tested were as follows: COMPOUNDS OF THE PRESENT APPLICATION Compound No.

I Ethyl 4-hydroxy-7-methoxy-6-n-octyloxy uinoline-3-carboxylate II Ethyl 4-hydro^-7-methoxy-6-n-nonyloxyquinoline-3^arboxylate III Ethyl 6-n^ecyloxy-4-hydroxy-7-methoxyquinoline-3-carboxylate IV Ethyl 7-etho-^^-hydroxy-6-n^ctylo-^quinoline-3-carboxylate V Ethyl 4-hydroxy-6-n-pctyloxy-7-n-propoxyquinoline-3-carboxylate VI Methyl 4-hydroxy-7—nethoxy—6-n-octyloxyquinoline-3-carboxylate VII Ethyl 4-hydroxy-7-isopropoxy-6-n-octyloxyquinoline-3-carboxylate VIII Methyl 7-ethoxy-4-hydroxy-6-n-octyloxyquinoline-3-carboxylate IX Methyl 4-hydroxy-7-methoxy-6-n-nonyloxyquinoline-3-carboxylate X Methyl 6-n-decyloxy-4-hydroxy-7-methoxyquinoline-3-carboxylate XI Methyl 6-n^ecyloxy-7-ethoxy-4-hydroxyquinoline-3-carboxylate XII Ethyl 6-n^ecyloxy-7-othoxy-4-hydroxyquinoline-3-carboxylate XIII Methyl 4-hydroxy-7-isopropoxy-6-n-octyloxyquinoline-3-carboxylate XIV Methyl 4-hydroxy-7-isopropoxy-6-n-nonyloxyquinoline-3-carboxylate XV Ethyl 4-hydroxy-7-isoprqpoxy-6-n-nonyloxyquinoline-3-carboxylate XVI * Ethyl 7-ethoxy-4-hydroxy-6-n-nonyloxyquinoline-3-darboxylate XVII Ethyl 6-n^ecyloxy-^l^droxy-7-isopropoxyquinoline-3--carboxylate XVIII Methyl 7-ethoxy-4-hydroxy-6-n-nonyloxyquinoline-3-carboxylate XIX Methyl 6-n-decyloxy-4-hydroxy-7-isopropoxyquinoline-3-carboxylate XX Ethyl 7-sec-butoxy-6-n^ecyloxy-4-hydroxyquinoline-3-carboxylate XXI Ethyl 6-n-decyloxy-4-hydroxy-7-n-propoxyquinoline-3-carboxylate OTHER COMPOUNDS WITHIN THE BROAD DISCLOSURE OF ISRAEL PATENT NO. 25347 Compound No.

XXII Ethyl 7-n-dodecyloxy-4-hydroxyquinoline-3-carboxylate XXIII Methyl e^T-di-n-decyloxy-^hydroxyquinolin^-carboxylate XnV Ethyl 6-n-hexyloxy-7-methoxy-4-^hydroxyquinoline-3-oarboxylate XXV Ethyl 6-n-pentyloxy-7-methoxy-4-hydroxyqxiinoline-3-carboxylate XXVI Ethyl 6,7-dibenzyloxy-4-hydroxyquinoline-3-carboxylate XXVII Ethyl 6~benzyloxy-7-methoxy-^hydroxyquinollne-3-carboxylate XXVIII Ethyl 6-methoxy-7-n^ctyloxy-4-hydroxyquinoline-3-carboxylate XXIX Ethyl 6-dodecyloxy-7-methoxy-4-hydroxyquinoline-3-carboxylate XXX Ethyl 6-(2-ethylbutoxy)-7-methoxy-4-hydroxyquinoline-3-carboxylate XXXI Ethyl 6-(l ,4-dimethyl pentyloxy)~7-methoxy-4-hydroxyquinoline- 3-carboxylate XXXII Ethyl 6-(i-ethyl hexyloxy)-7-methoxy-4-hydroxyquinoli e-3-carboxylate XXXIII Ethyl 6-(3,5,5-trimethylhexyloxy)-7-met^^ 3-carboxylate XXXIV Ethyl 6-(3,7-dimethyl octyloxy)-7-methoxy-4-hydroxyquinoiine- 3-carboxylate XXXV Ethyl 6,7-di-n-octyloxy-4-hydroxyquinoline-3-carboxylate XXXVI Ethyl 6-n-pentyloxy-7-ethoxy-4-hydroxyquinoline-3-carboxylate XXXVII Ethyl 6,7-di-n-decyloxy-4-hydroxyquinoline-3-carboxylate XXXVIII Ethyl 6,7-di-n-hexyloxy-4-hydroxyquinoline-3-carboxylate XXXIX Ethyl 6-octyloxy-7-benzyloxy-4-hydroxyquinoline-3-carboxylate XL Ethyl 6-benzyloxy-7-propoxy-4-hydroxyquinoline-3-carboxylate XLI Ethyl 6,7-bis(3,7-dimethyloctyloxy)-4-hydroxyquinoline-3-carboxylate XLII Ethyl 7-ethoxy-4~hydroxy-6-(3,5,5-trimethylhexyloxy)-quinoline-3- carboxylate The following test method was used: 6- or 7-day-old chicks, previously received as day-olds from a in le commercial hatcher were laced on test in ex erimental rooms maintains! at a temperature of approximately 90°F. and lit continuously with artificial light. The chicks were housed in groups of 5 (for Jjj^ tenella) or 4.. (for E. acervulina) in wire-floored metal cages, and in each test one group served as an unmedicated uninfected control and one as an unmedicated infected control.

Depending upon the concentration required of the compound under test, a 10 percent or lower concentration premix of each compound for testing was prepared in plain wheat flour by mixing with a pestle and mortar. From this premi the medicated diet was prepared by thorough mixing in an electric mixor with baby chick mash 'of the Houghton Poultry Research Station formula. This baby chick mash had the formula: Ingredient Weight * Middlings 13.41 Barley 13.41 Maize 13.41 Wheat 31.32 Fish meal 8.92 Soyabean meal 8.92 Dried grass meal 4,56 Unex. dried yeast 2.33 Dried skimmed milk powder 2.68 Salt 0.09 Limestone 0.89 Trace mineral suppl."^" 0.06 100.00 SUPPLEMENTS Vitamin A (i.u./kg. ) 4000 Vitamin D^ (i.u./kg. ) 1000 Choline chloride (mg. kg. ) 11 ,5 i' Trace mineral supplement provides per kg. ..of diet, .Mh 78 mg. , I 1 mg. , Zn 64 mg. .

Twenty-four hours after administration of the drug diet began, the chicks in the infected groups were each given orally a suspension containing approximately 25,000 sporulated oocysts of E.. tenella (Houghton strain) or 50,000 sporulated oocysts of E.. acervulina (Ongar strain). The medicated diet was fed throughout the test period. No separate experiments were performed to assess toxicity, as toxicity can be adequately detected during the tests.

The severity of the infection observed in the untreated control groups of chicks varied somewhat from experiment to experiment,. The following table gives the oocyst count or infection score for each series of controls (test number). Oocyst production and infection scores were determined as hereinafter indicated.

E. acervulina Test number Oocyst Production (millions per bird) of infected control 1 75.8 2 67.8 3 35.6 4 59.4 66.7 6 120.9 7 100.8 8 106.2 9 50.4 91 .2 1 ! 51.8 12 64.8 13 61.4 14 69.0 112.8 E« tenella The followin results were obtained; E. Acervulina E. Acervulina B. Acervulina -4-, E. Acervulina E. Acervulina E. Acorvulina E. Acervulina E. Acervulina E. Acervultna E. Acervulira Ε. AcervuLina E« Acervulina E. Acervulina En Acervulina E» Acervulina Ε. Tenella Ε. Tenella E. Tenella Hie activity of the compounds was evaluated as follows: E. acervulina.

The criterion of activity was a comparison, between the treated chicks and the untreated controls, of the total oocyst production on the 5th, 6th and 7th days after infection. The total faeces for each grou of chicks was separately collected on each of the specified days and preserved in 2.5 percent by weight aqueous potassium dichromate solution. On the last day the total numbers of oocysts in the pooled sample for each group were counted by the method of Long and Rowell (Lab. Pract. 7,515 (1958)).

The effective dose (EDQri) was defined as that concentration of the yu compound under test in the feed which reduced the total oocyst output by 90 percent compared with the unmedicated infected control. The compounds were initially tested at concentrations of 0.1, 0.01 and 0.001 percent w/w in the diet, and then in further tests at concentrations where the interval between drug levels was a factor of 2 or -^, to provide sufficient data for the plotting of a dose-response curve. All the results obtained were plotted graphically as the logarithm of the drug concentration against the probit of the percentage reduction of infection. For each compound a straight line (the regression line) was drawn by eye to fit the points as well as possible. The EDon (i.e. that concentration of compound under test which reduced total yu oocyst production by 90 ) was then measured from this line.

E. tenella Two criteria were used: (1) The severity of caecal lesions on the 7th day after infection (including chicks which died on the 5th-7th days) classified as follows:- 0 = no lesions; 1 = few lesions; often accompanied by slight haemorrhage, thickening of the caecal walls OB small caseous core; 2 = moderate number of lesions, often with caecal core; 8 = one chick dying from acute caecal coccidiosis; (2) The number of bloody droppingpassed during the 5th, 6th and 7th days of infection, classified as follows: 0 = no blood passed; 1 = 1 - 5 bloody droppings per group; 2 = 6 - 10 bloody droppings per group; 4 = more than 10 bloody droppings per group.

The EbQ(~ figures were then obtained graphically in the manner described above for E. acervulina by plotting the logarithm of the drug concentration against the percentage reduction of infection, calculated by comparing the added numerical values of the symptons (1) and (2) above (the infection score) for each group with the similarly combined value of the unmedicated control group symptoms.

The following results were obtained: E. acervulina COMPOUND M BER EDgQ (fo w/w) I 0.0054 II 0.0018 III 0.0025 IV 0.0015 V 0.0016 VI 0.0047 VIII 0.001 DC 0.00066 X 0.0012 XI 0.00027 XII 0.000 XIII 0.00012 E. acervuLina COMPOUMD MJMBER EDgo (flf/) XV 0.0002 XVI 0.0004 XVII 0.00012 XVIII 0.00022 XIX 0.00004 XX 0.00034 XXI 0.00056 XXII 0.01 XXIII >0.1 XXIV >0.1 XXV >0.1 XXVI >0.1 XXVII >0.1 XXVIII 0.0014 XXIX >0.1 XXX >0.1 XXXI >0.1 XXXII 0.024 XXXIII >0.1 XXXIV >0.1 XXXV > 0.1 XXXVI 0.023 XXXVII >0.1 XXXVIII >0.1 XXXIX . 0.015 XL >0.1 XLI >0.1 XLII >0.1 E. tenella COMPOUND NUMBER VII 0.00079 VIII 0,0014 XI 0.00017 XII 0.00037 XIII 0,00014 XLII > 0·1 The foregoing results show the unique and outstanding anti-coccidial activity of the compounds of general formula II wherein the 6-position is substituted by an alkoxy group containing 7 to 10 carbon atoms, and the 7-position is substituted by an alkoxy group of 1 to 4 carbon atoms.

Claims (1)

1. HAVING NOW particularly described end ascertained the nature of our said invention and in what manner the s&ae is to be performed, we declare that what we claim is 1, Quinoline derivatives of the general formula: wherein R represents a straight-chain alkyl group containing from 7 to 11 carbon ctoms, R^represents a straight- or branched-chain alkyl group containing from 1 to carbon atoms, and 2 represents a straight- or branched-chain alkyl group containing from 1 to 3 carbon atoms, and salts thereof, 2. Quinoline derivatives according to claim 1 wherein R is an n-octyl n-nonyl or n-decyl group, R^ is a methyl, ethyl, n-propyl, isopropyl or sec-butyl group, and ^ is a methyl or ethyl group. 3. Ethyl 6-n-decyloxy-7-ethoxy-l+-hydroxyquinoline-3-carboxylate. . Methyl 7-ethoxy-i+-hydroxy-6-n-octyloxyquinoline-3-carbox late . 5. Methyl 6-n-decyloxy-7-ethoxy-^-hydroxyquinoline-3-carboxylate . 6. Methyl -hydroxy-7-isopropoxy-6-n-octyloxyquinoline-3-carboxylate. 7. Ethyl i-hydroxy-7-isopropoxy-6-n-octyloxyquinoline-3-carboxylate. 8. Methyl 7-ethoxy- -hydroxy-6-n-nonyloxyquinoline-3-carboxylate, 9· Ethyl 7-ethoxy-i+-hydroxy-6-n-nonyloxyquinoline-3-carboxylate. 10. Methyl -hydroxy-7-isopropoxy-6-n-nonyloxyquinoline-3-carboxylate . 11. Ethyl if-hydroxy-7-isopropoxy-6-n-nonyloxyquinoline-3-carboxylate. 12. Methyl 6-n-decyloxy- hydroxy-7-isopropoxyquinoline-3-carboxylate . 1½. Ethyl 7-sec-butoxy-6-n-decyloxy-—hydroxyquinoline-3-carboxylate. 5. Ethyl i-hydroxy-7-raethoxy-6-n-nonyloxyquinoline-3-carboxylate. 16. Ethyl 17. Methyl L\—hydroxy-7-niethoxy-6-n-octyloxyquinoline-3-carboxylate . 18. Ethyl 7-ethoxy- -hydroxy-6-n-octyloxyquinoline-3-carboxylate . 1 . Ethyl ^-hydroxy -6-n-octyloxy-7-n-propoxyquinoline -3-carbox late. 20. Methyl i-hydroxy-7-methoxy-6-n-nonyloxyquinoline-3-carboxylate . 21. Methyl 6~n-decyloxy-i-hydroxy-7-methoxyquinoline-3-carboxylate. 22. Alkali metal salts of a quinoline derivative claimed in any one of the preceding claims. 23· Process for the preparation of quinoline derivatives of the general formula specified in claim 1 or salts thereof substantially as hereinbefore described. 2k. Process for the preparation of quinoline derivatives of the general formula specified in claim 1 or salts thereof substantially as described in any one of Examples I to XVI. 25· Quinoline derivatives of the general formula specified in claim 1,or salts thereof, when prepared by a process claimed in claim 23 or 2L\-or by any obvious chemical equivalent thereof. 26. A chicken feedstuff for use in the prevention of cocci di osis comprising , in coccidiost ati cally effective amount , at least one quinoline derivative conforming to the general formula specified in cl aim 1 , or non-toxic salt thereof . 27. A chicken feedstuff according to cl aim 26 , in which the concentration of the quinoline ingredient is from 0.0001% to 0.05% by wei ght of the feedstuff . 28. A chicken feedstuff according to claim 26 in which the concentration of the quinol ine ingredient i s from 0.001% to 0.025% by wei ght of the feedstuff . 29. A chicken feedstuff according to cl aim 26 , 27 or 28 in which the feedstuff is a chicken st arter , grower , layer or breeder feed. 30. A chicken feedstuff according to any one of claims 26 to 29 in which the quinoline ingredient is ethyl 6-n-decyloxy-7-ethoxy-4-hydroxyquinoline-3-carboxylate . 31. A chicken feedstuff according to any one of claims 26 to 29 in which the quinol ine ingredient is at least one of ethyl 4-hydroxy-7-isopropoxy-6-n-octylo.cyquinoline-3-carboxyl ato , methyl 4-hydroxy-7-i sopropoj-y-e-n-octyioxyquinoline-^-carboxj^late , methyl 7-ethoxy-4-hydroxy-6-n-octyloxyquinoline-3-carboxylate and methyl 6-n-decyloxy-7 -ethoxy-4-hy droxyqui nol i ne-3 -carboxy 1 at e . 32. A concentrate for addition to chicken feedstuff or drinking water comprisi ng 1% to 90% by wei ght of at least one quinoline derivative conforming to the general formula speci fied in claim 1 , or non-toxic salt thereof , in associ ation with a physiologically innocuous carrier. 33» A concentrate according to claim 32 containing from % to 30% by weight of quinoline compound. 34. A concentrate for addition to chicken feedstuff or drinking water comprising at least one quinoline derivative conforming to the general formula specified in claim 1, or non-toxic salt thereof, in association with on emulsifying, dispersing, suspending or wetting agent, with or without a physiologically innocuous carrier. 35 i concentrate according to claim 32, 33 or 34 wherein the physiologically innocuous carrier is solid or serai -solid. 36. A concentrate as claimed in any one of claims 32 to 35 in which the included quinoline derivative is ethyl 6-n-decyloxy-7-et oxy-4-hydro yquino1ine-3-carboxy1ate. 37» concentrate as claimed in any one of claims 32 to 35 in w] the included quinoline derivative is at least one of ethyl 4-hydroxy-7-isopropoxy-6-n-octyloxyquinoline-5-carboxylate , methyl 4-hydroxy-7-isopropoxy-6-n-octyloxyquinoline-3-carbo.ylate, methyl 7-ethoxy-4-hydroxy-6-n-octyloxyquinoline-3-carboxylate and methyl 6-n-decyloxy-7-ethoxy-4-hydro yquinoline~3-carboxylate. 38. Chicken feedstuffs, or concentrates for addition to chicken feedstuff3 or drinking water, according to claim 26, 32 or 3 substantially as hereinbefore described with especial reference to any one of Examples XVII to XXII 39» A method of preventing coccidiosis in chickens which comprises administering to the chickens a prophylactically effective amount of at least one quinoline derivative of the formula specified in claim 1, or non-toxic salt thereof. 4θ« A method according to claim 39 in which the said quinoline compound is administered in a chicken feedstuff or drinking v/ater containing 0,0001 to 0.05% by weight of quinoline compound. 41. A method according to claim 39 or 40 in which the said quinoline derivative is ethyl 6-n-decyloxy-7-ethoxy-4-hydroxyquinoline-3-carboxy1ate. 42. A method according to claim 39 or 40 in which the said quinoline derivative is ethyl 4-hydroxy-7-isopropoxy-6-n-octyloxy-quinoline-3-carboxylate , methyl 4-hydroxy-7-isopropoxy-6-n-octyloxy-quinoline-3-cnrboxylate, methyl 7-ethoxy-4-hydroxy-6-n-octyloxy-quinoline-3-carboxylate or methyl 6-n-decyloxy-7-ethoxy-4-hydroxy-quinoline-3-carboxyl te , Dated thie lenth day of Mey 1967 Agent for Applicants